Tempol provides selective protection to normal tissue during fractionated Irradiation

Objective: Radiotherapy is commonly used to treat a majority of patients with head and neck cancers. Salivary glands in the irradiation (IR) field are dramatically affected by this procedure. Current management approaches are unsatisfactory. The purpose of the present pre-clinical study was to determine whether Tempol, shown to provide radioprotection to salivary glands (Cotrim et al, Clin Cancer Res, 2005), would also protect tumor when administered to C3H mice 10 min prior to each of 5 daily IR fractions. Materials and methods: The heads of C3H mice were exposed to a total dose of 30 Gy (5 x 6 Gy daily fractions) with and without Tempol (275 mg/kg, i.p.) treatment. Salivary gland function (pilocarpine-induced saliva collection over 10 min) was measured 8 weeks later. Next, mice presenting a tumor in the proximal portion of the front limb (SCCVII tumor, 8 mm diameter) were locally treated with fractionated radiation (5 x 3 Gy daily fractions) with and without Tempol treatment and delay in tumor regrowth was assessed. Results: Tempol treatment provided significant radioprotection against salivary gland damage (saliva output: 291±23.6, 113.1±14.8, and 226.3±18 µl for non-irradiated, irradiated, and irradiated Tempol-treated animals, respectively, n=8/group). Tempol treatment 10 min prior to IR did not protect against radiation-induced tumor regrowth delay. The mechanism for the selective normal tissue radioprotection may be explained by the different Tempol reduction rates in normal tissue versus tumor tissue. The hypoxic tumor environment leads to a faster reduction of Tempol than occurs in normal tissue. When Tempol is administered 10 min prior to IR, significant levels of biologically active compound can still be found in normal tissue, whereas in tumor tissue the Tempol has been already reduced. Conclusion: These pre-clinical studies support the use of the stable nitroxide Tempol as a selective normal tissue radioprotector worthy of clinical evaluation.